1,720,962 research outputs found
A functional study of disease-causing GNB1 mutations
No full textG protein-coupled receptors (GPCRs) represent the largest class of membrane receptors in eukaryotes. Activation of GPCRs by extracellular signals leads to conformational changes that activate the associated G protein heterotrimer, composed of the Ga and Gbg subunits. Mutations in the Gb1 subunit have been implicated with a number of different cancers and neurodevelopmental disorders. We focused on a set of ten germline and somatic de novo Gb1 point mutations studying their effects in vitro, with a view toward functionally classifying them. Our objectives were to map functional regions, and connect functional outcomes to clinical phenotypes. We hypothesized that disease-causing Gb1 mutations confer gains or losses of function that impact their interactions with partners and their effects on signalling pathways. We generated flag-tagged, siRNA-resistant versions of wildtype (WT) and mutated Gb subunits, to study them in a background of reduced endogenous Gb1 subunit expression. Our first functional investigation was on intracellular calcium release in response to M3-mAChR stimulation, because calcium signaling has been linked to both cancer and neurological disorders. Previous work in the lab has shown that knockdown of the Gb1 subunit leads to a significant increase in intracellular calcium release in response to carbachol treatment. Expression of the siRNA-resistant WT-Gb1 rescued the increase in calcium release caused by WT-Gb1 knockdown. We were able to classify Gb1 as D76G and I80T resulted in a loss of function, whereas K57E, K78E and K89E exhibited a dominant negative effect, causing changes in baseline calcium signalling.Next, we assessed whether interactions with Gaq/11 and RNA polymerase II (RNAPII) are affected by mutations in Gb1. We used co-immunoprecipitation to identify which mutations physically interact with Gaq/11, the principal Ga subunit implicated in PLC activation. Only Gb1 mutants I269T, D76G and A11V maintained a strong interaction with Gaq/11. This suggests that G1 is involved in the PLC signaling pathway independently of a Gaq/11 interaction, which supports previous work which has shown that Gb1 modulates calcium release by regulating the expression of Gb4. In fact, Gbg plays an important role in transcription, occupying over 700 promoters and interacting with RNAPII. We used co-immunoprecipitation to verify if the Gb1 mutations were able to interact with RNAPII. We found that all of them were, however, none of the showed the same increase in the interaction seen with WT-Gb1 in response to M3 mAChR stimulation. In contrast, mutations D76G and K57E had a reduced interaction under carbachol treatment. In conclusion, we investigated several interacting partners and signaling pathways downstream of Gb1, to classify Gb1 mutations as causing gains or losses of function. Our work helped map functional regions along the gene, and draw some links between the functional outcomes and clinical phenotypes caused by the mutations.Les récepteurs couplés aux protéines G (RCPGs) représentent la plus grande classe de récepteurs membranaires chez les eucaryotes. L'activation des RCPGs par des signaux extracellulaires conduit à des changements conformationnels qui activent l'hétérotrimère des protéines G associées, composé des sous-unités Ga et Gbg. Des mutations de la sous-unité Gb1 ont été impliquées dans un certain nombre de cancers et des troubles du développement neurologique. Nous nous sommes concentrés sur un ensemble de dix mutations ponctuelles germinales et somatiques de novo Gb1, dans le but d’étudier leurs effets in vitro, en vue de leur classification fonctionnelle. Nos objectifs étaient de cartographier les régions fonctionnelles et de relier les résultats fonctionnels aux phénotypes cliniques. Nous avons émis l'hypothèse que les mutations Gb1 causant des maladies confèrent des gains ou des pertes de fonction qui ont une incidence sur leurs interactions avec les partenaires et leurs effets sur les voies de signalisation. Nous avons généré des versions de type naturel (WT) et de sous-unités Gb1 mutées, marquées par flag et résistantes au siRNA, afin de les étudier dans un contexte d'expression de sous-unité Gb1 endogène réduite.Notre première étude fonctionnelle portait sur la libération de calcium intracellulaire en réponse à la stimulation M3-mAChR, car la signalisation du calcium a été démontrée liée au développement des cancers et des troubles neurologiques. Des travaux antérieurs dans notre laboratoire ont montré que l'inactivation de la sous-unité Gb1 entraîne une augmentation significative de la libération de calcium intracellulaire en réponse au traitement avec le carbachol. Cet effet a été renversé par la surexpression du Gb1-WT résistant au siRNA. Nous avons pu classer Gb1 dans les catégories D76G et I80T entraînant une perte de fonction, alors que K57E, K78E et K89E présentaient un effet négatif dominant, provoquant des changements dans la libération basale de calcium.Ensuite, nous avons évalué l’incidence des mutations de Gb1 sur les interactions avec Gaq/11 et l'ARN polymérase II (ARNPII). Nous avons utilisé la co-immunoprécipitation pour identifier les mutations qui interagissent physiquement avec Gaq/11, la principale sous-unité G impliquée dans l'activation de la phospholipase C (PLC). Seuls les mutants Gb1, I269T, D76G et A11V ont maintenu une interaction forte avec Gaq/11. Cela suggère que Gb1 est impliqués dans la voie de signalisation de la PLC indépendamment de Gaq/11, ce qui concorde avec des travaux précédents qui ont montré que Gb1 module la libération de calcium en régulant l'expression de Gb4. En effet, Gbg joue un rôle important dans la transcription, occupant plus de 700 promoteurs et interagissant avec l’ARNPII. Nous avons utilisé la co-immunoprécipitation pour vérifier si les mutations Gb1 étaient capables d'interagir avec ARNPII. Nous avons constaté qu’elles l’étaient toutes, cependant, elles ne présentaient pas la même augmentation d'interaction observée avec WT-Gb1 en réponse à la stimulation de M3 mAChR. En revanche, les mutations D76G et K57E montraient une interaction réduite sous traitement au carbachol. En conclusion, nous avons étudié plusieurs partenaires en interaction et voies de signalisation en aval de Gb1, afin de classer les mutations de Gb1 entraînant des gains ou des pertes de fonction. Grace à cette étude, nous avons pu cartographier les régions fonctionnelles le long du gène et établir des liens entre les résultats fonctionnels et les phénotypes cliniques causés par les mutations
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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